By Timothy Vartanian, MD, PhD
Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director, Judith Jaffe Multiple Sclerosis Center
SYNOPSIS: In this small study of the effect of mesenchymal stem cell treatment, both intravenous and intrathecal, in patients with progressive multiple sclerosis, the treatment was shown to be safe, and there was a trend showing some benefit in slowing disease progression, compared to the sham group. A larger randomized controlled trial is needed to confirm these early findings.
SOURCE: Petrou P, Kassis I, Levin N, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain 2020:143;3574-3588.
Progressive forms of multiple sclerosis (MS) largely remain refractory to treatment. Two clinical trials (anti-CD20 in primary progressive MS, and S1P antagonist in secondary progressive MS) have reported a benefit of disease-modifying therapies in progressive MS. However, in both of these progressive trials, clinical benefit, in part, seemed to be driven by the effects of these agents on relapsing-remitting pathophysiology based on subgroup analysis of patients with gadolinium contrast enhancing lesions and new and enlarging T2 lesions.
This all begs the question as to whether we truly are able to effectively target the underlying pathophysiology of progressive MS and achieve meaningful clinical effect. Autologous mesenchymal stem cell (MSC) transplantation has shown promise in animal models, but results from human studies have been mixed. The MSC study reported by Petrou et al is intriguing and certainly warrants a larger, multisite study. In this study, 200 patients were screened, 152 patients were excluded, and 48 patients were enrolled into three groups: placebo, MSC administered intravenously (MSC-IV), and MSC administered intrathecally (MSC-IT). Following randomization, patients were treated with placebo, MSC-IV, or MSC-IT for six months, at which time each of the three initial treatment groups (n = 16 per group) were subdivided for treatment during the second six months: 16 placebo moved into eight MSC-IV and eight MSC-IT; 16 MSC-IV moved into eight MSC-IV and eight placebo; and 16 MSC-IT moved into eight MSC-IT and eight placebo. The primary endpoints were safety and progression on the Expanded Disability Status Scale (EDSS). The inclusion criteria in this study are important to understand and required either a diagnosis of active progressive MS (evidence of relapse or magnetic resonance imaging [MRI] activity) or worsening on the EDSS based on the revised designation of progressive MS subtypes.1
The results of the study are intriguing. With respect to safety, overall, the study supported the safety of MSC transplant IV or IT. There were three serious adverse events: an upper respiratory tract infection and two MS relapses requiring hospitalization. Of the two serious relapses, one occurred in the placebo group in the first six months (during the placebo phase of this group) and the second occurred in the MSC-IT group during the MSC-IT cycle. In terms of efficacy, an analysis of the percentage of patients showing treatment failure defined as an increase in EDSS score of one point for patients with baseline EDSS values ≤ 5, and half a point for patients with baseline EDSS values > 5.0. The EDSS ascertainment was performed at the end of the six-month treatment periods; that is, at six and 12 months. Treatment failure was significantly lower in the MSC-IT (6.7%) and MSC-IV groups (9.7%) compared with the placebo-treated patients (41.9%), and there was no significant difference between the IT and IV groups. Similar benefit was observed in the analysis of the functional systems scores. Analysis of the timed 25-foot walk, nine-hole peg test, and ambulation index all supported the active treatment arms.
Significantly more patients in the MSC-IT and MSC-IV groups showed improvement in EDSS compared to those who received sham treatment by approximately 0.4 to 0.5 EDSS point at six months. Although these might not seem to be large changes, this study is of relatively short duration for a progressive trial, and observable treatment effects in this time frame are impressive.
However, the question remains, is the treatment targeting relapsing-remitting pathophysiology, progressive pathophysiology, or potentially both? Relapsing-remitting pathophysiology is the most thoroughly studied in MS and consists of focal or multifocal inflammatory demyelination centered on a post-capillary venule with some degree of associated axonal injury. Progressive pathophysiology in MS is not so clearly defined, but many high-quality studies support gradual neurodegeneration as the result of oxidative and metabolic stress associated with the chronically demyelinated axon and smoldering innate immune activity. It is useful to look at indicators of relapsing-remitting pathophysiology, such as relapse rate (relapses per patient in this study), new or enlarging T2 lesions, or gadolinium contrast enhancing lesions. Relapses per patient were reduced in the MSC-IT vs. sham group (0.06 vs. 0.56) which was highly significant. For the MSC-IV vs. sham group, the relapse per patient results trended to significance (0.28 vs. 0.56, P = 0.052).
A significant change was observed in the T2 lesion volume change comparing MSC-IT vs. sham, but not MSC-IV vs. sham. These results show that some of the benefit of active treatment probably comes from affecting relapsing-remitting pathophysiology.
Important features of this study are the rigorous efforts toward adequate blinding of subjects and the examining neurologist. In addition, the size of the study exceeds many of the previously published stem cell trials in MS. Finally, the thorough analysis of clinical and MRI parameters provides the reader with sufficient data to assess results.
The results of the Petrou et al study are promising and certainly warrant a larger, multisite, double-blinded study of autologous MSC transplantation in MS. The problem with almost all progressive studies in MS is the relatively high degree of relapsing-remitting disease activity that exists in the study population, which always leads to ambiguity as to whether the treatment effect is on relapsing disease or progressive disease. I favor a study design that excludes patients with any evidence of relapsing-remitting disease activity in the two years prior to initiating treatment and examines the treatment effect to the best degree possible in a patient population or in functional systems that are solely progressive.
- Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology 2014;83:278-286.